PROJECT SUMMARY ? Project 4 In spite of substantial research effort, cocaine dependence is a particularly difficult substance use disorder to treat. Preclinical models in the Center demonstrate that decreasing neuronal activity in the ventromedial prefrontal cortex (vmPFC) and ventral striatum (i.e. nucleus accumbens core), henceforth corticostriatal circuit, block cocaine cue-induced reinstatement. The scientific and clinical premise of Project 4 is that targeted inhibition of the corticostriatal circuit will dampen cocaine cue-induced craving in cocaine users. Continuous theta burst stimulation (cTBS) is a form of repetitive transcranial magnetic stimulation that induces long term depression-like (LTD-like) decreases in neural excitability in the area stimulated and downstream monosynaptic targets. A single dose of cTBS to the vmPFC selectively decreases activity in the ventral striatum and self-reported craving. Recently, we found that N- acetylcysteine (NAC) increases corticostriatal resting state functional connectivity (rsFC) in nicotine users concomitant with reducing craving. The overarching goals of Project 4 are to evaluate the efficacy of combined cTBS+NAC on addiction pathophysiology in corticostriatal circuitry, and to bidirectionally translate our findings with the preclinical COCA Projects. We will determine if LTD-like cTBS decreases cocaine cue reactivity in cocaine dependent individuals (Aim1), and if NAC strengthens corticostriatal rsFC (Aim 2). Then, we will examine the efficacy of cTBS+NAC to synergistically reduce drug cue reactivity and craving (Aim 3). These aims will be evaluated through a double blinded (TMS: TBS vs. SHAM; Medication: NAC vs. Placebo: PBO) study in 96 cocaine dependent individuals. All individuals will undergo an fMRI baseline scan and then randomized to one of 4 groups: 1) NAC + TBS, 2) NAC + Sham, 3) PBO + TBS, 4) PBO + Sham). As these data emerge, we will work closely with preclinical Projects 1-3 to provide these projects with human circuitry data that can help guide their studies. Conversely, we will receive data regarding corticostriatal mechanisms generated in rodent models of relapse that can inform the interpretations of our clinical data and guide our research through greater understanding of the underpinning molecular and circuit level neurobiology.